Project Summary/Abstract Site-selective functionalization of aliphatic C?H bonds can provide shortcuts to the synthesis of bioactive molecules, including those that cannot be feasibly or practically made using other synthetic approaches. Given the prevalence of nitrogen- and oxygen-containing functional groups in approved drugs, the importance of developing general methods for aliphatic C?H amination and hydroxylation in particular is widely recognized. Although catalytic methods for both selective intermolecular and directed C?H hydroxylations of aliphatic C?H bonds have been successfully developed, their generality is greatly limited by a lack of functional group compatibility and limited ability to override substrate control of selectivity. Similar challenges exist for aliphatic C?H amination, and they are comparatively greater given that only a handful of site-selective methods have yet been reported. As such, new catalytic methods for selective aliphatic C?H hydroxylation and amination that are more tolerant of a wide range of functional groups and that are amenable to new strategies to control site selectivity will greatly improve the generality and scope of this synthetic approach. In turn, these new methods will improve the ability of synthetic chemists to efficiently synthesize therapeutic leads. We propose a new, unified catalytic strategy to achieve site-selective aliphatic hydroxylation and amination. The strategy features the use of iminium salt organocatalysts developed in our lab, that we have discovered overcome functional group compatibility issues inherent to other catalytic methods. The objective of Aim 1 is to develop iminium salt-catalyzed intermolecular site-selective hydroxylation reactions that are compatible with alcohol functional groups, including hydroxylations of methylene C?H bonds that are selective for alcohol products. The objective of Aim 2 is to develop intermolecular iminium salt-catalyzed amidation reactions that are selective for one of many sp3 C?H bonds. Finally, the objective of Aim 3 is to apply these organocatalytic methods to directed aliphatic C?H hydroxylations and aminations to achieve remote functionalizations of aldehyde and ketone substrates that are not addressed by existing catalytic methods. The proposed research will result in new methods for accessing synthons common to bioactive molecules and new methods for the late-stage diversification of therapeutic leads.